Publications by authors named "Frits R Rosendaal"

470 Publications

Associations of metabolomic profiles with circulating vitamin E and urinary vitamin E metabolites in middle-aged individuals.

Nutrition 2021 Jul 29;93:111440. Epub 2021 Jul 29.

Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

Vitamin E (α-tocopherol [α-TOH]) is transported in lipoprotein particles in blood, but little is known about the transportation of its oxidized metabolites. In the Netherlands Epidemiology of Obesity Study, we aimed to investigate the associations of 147 circulating metabolomic measures obtained through targeted nuclear magnetic resonance with serum α-TOH and its urinary enzymatic (α-CEHC) and oxidized (α-TLHQ) metabolites from 24-h urine quantified by liquid chromatography with tandem mass spectrometry. Multivariable linear regression analyses, in which multiple testing was taken into account, were performed to assess associations between metabolomic measures (determinants; standardized to mean = 0, SD = 1) and vitamin E metabolites (outcomes), adjusted for demographic factors. We analyzed 474 individuals (55% women, 45% men) with a mean (SD) age of 55.7 (6.0) y. Out of 147 metabolomic measures, 106 were associated (P < 1.34 × 10) with serum α-TOH (median β [interquartile range] = 0.416 [0.383-0.466]), predominantly lipoproteins associated with higher α-TOH. The associations of metabolomic measures with urinary α-CEHC have directions similar to those with α-TOH, but effect sizes were smaller and non-significant (median β [interquartile range] = 0.065 [0.047-0.084]). However, associations of metabolomic measures with urinary α-TLHQ were markedly different from those with both serum α-TOH and urinary α-CEHC, with negative and small-to-null relations to most very-low-density lipoproteins and amino acids. Therefore, our results highlight the differences in the lipoproteins involved in the transportation of circulating α-TOH and oxidized vitamin E metabolites. This indicates that circulating α-TOH may be representative of the enzymatic but not the antioxidative function of vitamin E.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nut.2021.111440DOI Listing
July 2021

Hepatitis C Virus Reactivation Following COVID-19 Vaccination - A Case Report.

Int Med Case Rep J 2021 29;14:573-576. Epub 2021 Aug 29.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection impacted morbidity and mortality during the pandemic of 2020-2021. A number of anti-COVID-19 vaccines have been developed with an unprecedented speed. While these vaccines have good efficacy and are safe, the experience with their use is limited and hence the knowledge of rare side effects. Identifying rare complications is important for future safe use of these vaccines.

Materials And Methods: Here, we report a case of a 82-year old patient with dementia who was admitted to a nursing home in the Netherlands. After vaccination with COVID-19 vaccination, physical examinations and lab tests were performed.

Results: She had a reactivation of hepatitis C infection after vaccination with the mRNA-based Pfizer-BioNTech COVID-19 vaccine. This reactivation manifested with jaundice, loss of consciousness, hepatic coma and death.

Conclusion: This reactivation of hepatitis C virus after vaccination with the Pfizer-BioNTech COVID‑19 vaccine suggests a need for critical consideration of individuals with prior HCV infection and considered for COVID-19 vaccination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IMCRJ.S328482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412816PMC
August 2021

Prediction or causality? A scoping review of their conflation within current observational research.

Eur J Epidemiol 2021 Aug 15. Epub 2021 Aug 15.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

Etiological research aims to uncover causal effects, whilst prediction research aims to forecast an outcome with the best accuracy. Causal and prediction research usually require different methods, and yet their findings may get conflated when reported and interpreted. The aim of the current study is to quantify the frequency of conflation between etiological and prediction research, to discuss common underlying mistakes and provide recommendations on how to avoid these. Observational cohort studies published in January 2018 in the top-ranked journals of six distinct medical fields (Cardiology, Clinical Epidemiology, Clinical Neurology, General and Internal Medicine, Nephrology and Surgery) were included for the current scoping review. Data on conflation was extracted through signaling questions. In total, 180 studies were included. Overall, 26% (n = 46) contained conflation between etiology and prediction. The frequency of conflation varied across medical field and journal impact factor. From the causal studies 22% was conflated, mainly due to the selection of covariates based on their ability to predict without taking the causal structure into account. Within prediction studies 38% was conflated, the most frequent reason was a causal interpretation of covariates included in a prediction model. Conflation of etiology and prediction is a common methodological error in observational medical research and more frequent in prediction studies. As this may lead to biased estimations and erroneous conclusions, researchers must be careful when designing, interpreting and disseminating their research to ensure this conflation is avoided.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10654-021-00794-wDOI Listing
August 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Microvascular differences in individuals with obesity at risk of developing cardiovascular disease.

Obesity (Silver Spring) 2021 Sep 2;29(9):1439-1444. Epub 2021 Aug 2.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.

Objective: This study aimed to investigate microvascular differences in individuals with obesity at risk for developing cardiovascular disease.

Methods: In this cross-sectional Netherlands Epidemiology of Obesity study, participant sublingual microcirculation was assessed with a newly developed GlycoCheck software (Microvascular Health Solutions Inc., Salt Lake City, Utah), which integrates red blood cell velocity within the smallest capillaries (4-7 µm) and feed vessels (>10 µm). Framingham Risk Score was used to calculate 10-year cardiovascular risk, divided into low-, intermediate-, and high-risk groups. ANOVA was used to evaluate microvascular differences among the groups.

Results: A total of 813 participants were included. The high-risk group (n = 168) was characterized by differences in the microvasculature compared with the low-risk group (n = 392): the high-risk group had a 49% reduction in the number of smallest capillaries and a 9.1-µm/s (95% CI: 5.2-12.9) higher red blood cell velocity in the feed vessels. No differences in velocity-corrected perfused boundary regions were found.

Conclusions: It was observed that, with adding red blood cell velocity to the software, sidestream dark field imaging is able to detect microcirculatory differences in a cohort of individuals with obesity at risk for developing cardiovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/oby.23222DOI Listing
September 2021

Publishing for science or science for publications? The role of open science to reduce research waste.

J Thromb Haemost 2021 08;19(8):1872-1873

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362099PMC
August 2021

Estimated pulse wave velocity (ePWV) as a potential gatekeeper for MRI-assessed PWV: a linear and deep neural network based approach in 2254 participants of the Netherlands Epidemiology of Obesity study.

Int J Cardiovasc Imaging 2021 Jul 25. Epub 2021 Jul 25.

Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Pulse wave velocity (PWV) assessed by magnetic resonance imaging (MRI) is a prognostic marker for cardiovascular events. Prediction modelling could enable indirect PWV assessment based on clinical and anthropometric data. The aim was to calculate estimated-PWV (ePWV) based on clinical and anthropometric measures using linear ridge regression as well as a Deep Neural Network (DNN) and to determine the cut-off which provides optimal discriminative performance between lower and higher PWV values. In total 2254 participants from the Netherlands Epidemiology of Obesity study were included (age 45-65 years, 51% male). Both a basic and expanded prediction model were developed. PWV was estimated using linear ridge regression and DNN. External validation was performed in 114 participants (age 30-70 years, 54% female). Performance was compared between models and estimation accuracy was evaluated by ROC-curves. A cut-off for optimal discriminative performance was determined using Youden's index. The basic ridge regression model provided an adjusted R of 0.33 and bias of < 0.001, the expanded model did not add predictive performance. Basic and expanded DNN models showed similar model performance. Optimal discriminative performance was found for PWV < 6.7 m/s. In external validation expanded ridge regression provided the best performance of the four models (adjusted R: 0.29). All models showed good discriminative performance for PWV < 6.7 m/s (AUC range 0.81-0.89). ePWV showed good discriminative performance with regard to differentiating individuals with lower PWV values (< 6.7 m/s) from those with higher values, and could function as gatekeeper in selecting patients who benefit from further MRI-based PWV assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10554-021-02359-0DOI Listing
July 2021

Real-time versus static scoring in musculoskeletal ultrasonography in patients with inflammatory hand osteoarthritis.

Rheumatology (Oxford) 2021 Jul 15. Epub 2021 Jul 15.

Leiden University Medical Center, Leiden, Netherlands.

Objectives: Agreement between real-time and static ultrasonographic has not been studied in musculoskeletal diseases. We studied this agreement in inflammatory hand osteoarthritis.

Methods: Ultrasonography was performed blinded to clinical information of 30 joints of 75 patients with hand osteoarthritis, treated with prednisolone in a randomized placebo-controlled double-blind trial. Images were scored real-time at acquisition and stored images were scored static (paired in known chronological order) for inflammatory features and osteophytes (score 0-3). Agreement between methods was studied at joint level with quadratic weighted kappa. At patient level intra-class correlations (ICC) of sum scores and change in sum-scores (delta baseline-week 6) were calculated. Responsiveness of scoring methods was analyzed with generalized estimating equations (GEE) with treatment as independent and ultrasonography findings as dependent variable.

Results: Agreement at baseline was good to excellent at joint level (kappa 0.72-0.88) and moderate to excellent at patient level (ICC 0.58-0.91). Agreement for change in sum scores was poor to fair for synovial thickening and effusion (ICC 0.18 and 0.34 respectively), while excellent for Doppler signal (ICC 0.80). Real-time ultrasonography discriminated between prednisolone and placebo with a mean between-group difference of synovial thickening of -2.5 (CI:-4.7 to-0.3). Static ultrasonography did not show a decrease in synovial thickening.

Conclusion: While cross-sectional agreement between real-time and static ultrasonography is good, static ultrasonography measurement of synovial thickening did not show responsiveness to prednisone therapy while real-time ultrasonography did. Therefore, when ultrasonography is used in clinical trials, real-time dynamic scoring should remain the standard for now.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keab556DOI Listing
July 2021

D-dimer, thrombin generation, and risk of a first venous thrombosis in the elderly.

Res Pract Thromb Haemost 2021 Jul 21;5(5):e12536. Epub 2021 Jun 21.

Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands.

Background: A high D-dimer level and parameters of the thrombin generation (TG) potential are associated with the risk of a first venous thrombosis (VT) in young and middle-aged populations.

Objectives: To investigate whether D-dimer and TG potential (lag-time, time-to-peak [ttPeak], peak thrombin, endogenous thrombin potential [ETP], and velocity index), are associated with the risk of a first VT in those aged 70 years and older.

Methods: We included 215 patients with a first VT and 358 controls, all aged >70 years, from the Age and Thrombosis, Acquired and Genetic Risk Factors in the Elderly (AT-AGE) study. To assess the risk of VT, odds ratios with 95% confidence intervals (CIs) were estimated using logistic regression analysis.

Results: D-dimer and all TG parameters except lag time were associated with an increased risk of VT in a dose-response manner. Comparing the fourth with the first quartile (for ttPeak comparing the first with the fourth quartile), risk estimates were: 7.8 (95% CI, 4.0-15.0) for peak, 2.0 (95% CI, 1.2-3.3) for ttPeak, 9.1 (95% CI, 4.4-18.9) for ETP, and 11.5 (95% CI, 5.7-23.3) for velocity index. Comparing the highest quartile of D-dimer with the lowest, the risk was 7.7-fold increased (95% CI, 4.0-14.8). Furthermore, all factors also increased the risk of VT after dichotomizing at more extreme cutoff values. The risk of VT was further increased in the presence of multiple prothrombotic TG parameters and elevated D-dimer level or in combination with prothrombotic mutations.

Conclusions: D-dimer and TG parameters (except lag time) are associated with the risk of first VT in elderly population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/rth2.12536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268666PMC
July 2021

Validation of PROMIS Profile-29 in adults with hemophilia in the Netherlands.

J Thromb Haemost 2021 Jul 10. Epub 2021 Jul 10.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

Background: The Patient-Reported Outcomes Measurement Information System (PROMIS) Profile-29 questionnaire is widely used worldwide, but it has not yet been validated in the Netherlands, nor in persons with hemophilia.

Objective: To validate the Dutch-Flemish version of the PROMIS-29 Profile v2.01 in adults with hemophilia.

Methods: Dutch males with hemophilia (all severities) completed questionnaires that contained sociodemographic and clinical characteristics, the PROMIS-29, RAND-36, and the Hemophilia Activities List (HAL). Structural validity of each subscale was assessed with confirmatory factor analysis (CFA). Internal consistency was calculated for each subscale with sufficient model fit in CFA. Construct validity was assessed by testing hypotheses about (1) correlations of each PROMIS-29 subscale with corresponding scales of RAND-36 and domains of HAL, and (2) mean differences in T-scores between subgroups with different hemophilia severities, self-reported joint impairment, and HIV infection status. We considered ≥75% of data in accordance with the hypotheses evidence for construct validity.

Results: In total, 770 persons with hemophilia participated in this cross-sectional study. CFA revealed sufficient structural validity for five subscales: Physical Function, Depression, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Pain Interference. Internal consistency was high and Cronbach's alpha ranged from 0.79 for Sleep Disturbance to 0.96 for Pain Interference. Differences between clinical subgroups were in the expected direction. Construct validity was confirmed for Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, and Pain Intensity.

Conclusion: This study revealed sufficient evidence for structural validity, internal consistency, and construct validity for most PROMIS Profile-29 subscales among people with hemophilia in the Netherlands.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15454DOI Listing
July 2021

The Relation Between Adult Weight Gain, Adipocyte Volume And The Metabolic Profile At Middle Age.

J Clin Endocrinol Metab 2021 Jun 28. Epub 2021 Jun 28.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Purpose: Weight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy. We aimed to study the specific metabolomic profile of adult weight gain, and to examine its association with adipocyte volume.

Methods: Nuclear magnetic resonance-based metabolomics were measured in the Netherlands Epidemiology of Obesity (NEO) study (n=6 347, discovery) and Oxford Biobank (n=6 317, replication). Adult weight gain was calculated as the absolute difference between BMI at middle age and recalled BMI at age 20. We performed linear regression analyses with both exposures BMI at age 20 years and weight gain, and separately with BMI at middle age in relation to 149 serum metabolomic measures, adjusted for age, sex and multiple testing. Additionally, subcutaneous abdominal adipocyte biopsies were collected in a subset of the Oxford Biobank (n=114) to estimate adipocyte volume.

Results: Mean (SD) weight gain was 4.5 (3.7) kg/m2 in the NEO study and 3.6 (3.7) kg/m2 in the Oxford Biobank. Weight gain, and not BMI at age 20 nor middle age, was associated with concentrations of 7 metabolomic measures after successful replication, which included polyunsaturated fatty acids, small to medium low-density lipoproteins and total intermediate-density lipoprotein. One SD weight gain was associated with 386 μm3 (95% CI 143 - 629) higher median adipocyte volume. Adipocyte volume was associated with lipoprotein particles specific for adult weight gain.

Main Conclusions: Adult weight gain is associated with specific metabolomic alterations of which the higher lipoprotein concentrations were likely contributed by larger adipocyte volumes, presumably linking weight gain to cardiometabolic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab477DOI Listing
June 2021

Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache.

Ann Neurol 2021 Aug 14;90(2):203-216. Epub 2021 Jul 14.

Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

Objective: Identifying common genetic variants that confer genetic risk for cluster headache.

Methods: We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses.

Results: An association was found with cluster headache for 4 independent loci (r  < 0.1) with genomewide significance (p < 5 × 10 ), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33-1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r  = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients.

Interpretation: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203-216.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.26146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362054PMC
August 2021

Differential effect of statin use on coagulation markers: an active comparative analysis in the NEO study.

Thromb J 2021 Jun 27;19(1):45. Epub 2021 Jun 27.

Department of Clinical Epidemiology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.

Background: Statins are a potential treatment for venous thromboembolism (VTE) prophylaxis complementary to conventional anticoagulants without associated bleeding complications. This study aimed to compare pro-thrombotic activities of different classes of lipid-lowering drugs in an active comparator design and determine whether there is a relation between statin versus fibrate/niacin use and pro-coagulant factor outcomes.

Methods: This is a cross-sectional analysis of participants from the Netherlands Epidemiology of Obesity study using any class of lipid-lowering drugs, including any types of statins, niacin, and fibrates. We performed linear regression analyses to determine fibrinogen, factor (F) VIII, FIX, and FXI activity in statins versus fibrate/niacin users and adjusted for age, sex, tobacco smoking, body mass index (BMI), hypertension, diabetes, and prevalent cardiovascular disease.

Results: Among 1043 participants, the mean age was 58.4 ± 5.2 years, 61% were men, and the mean BMI was 31.3 ± 4.5 kg/m. Clinical characteristics were balanced between statin and fibrate/niacin users. Statin users had lower mean FXI (18.3 IU/dL, 95% confidence interval (CI) 9.4 to 27.3) levels compared to fibrate/niacin users. The level of FVIII (15.8 IU/dL, 95% CI - 0.003 to 31.6), and FIX (11.3 IU/dL, 95% CI - 0.4 to 23.2) were lower in statin users than fibrate/niacin users with marginal statistical significance.

Conclusion: Current statin use was associated with lower plasma levels of FXI than fibrate/niacin use. The effects on coagulation factors may, in part, explain the benefit of statin therapy rendered in primary and secondary prevention of VTE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12959-021-00299-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237446PMC
June 2021

Association of measures of body fat with serum alpha-tocopherol and its metabolites in middle-aged individuals.

Nutr Metab Cardiovasc Dis 2021 07 18;31(8):2407-2415. Epub 2021 May 18.

Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background And Aims: The accumulation of fat increases the formation of lipid peroxides, which are partly scavenged by alpha-tocopherol (α-TOH). Here, we aimed to investigate the associations between different measures of (abdominal) fat and levels of urinary α-TOH metabolites in middle-aged individuals.

Methods And Results: In this cross-sectional analysis in the Netherlands Epidemiology of Obesity study (N = 511, 53% women; mean [SD] age of 55 [6.1] years), serum α-TOH and α-TOH metabolites from 24-h urine were measured as alpha-tocopheronolactone hydroquinone (α-TLHQ, oxidized) and alpha-carboxymethyl-hydroxychroman (α-CEHC, enzymatically converted) using liquid-chromatography-tandem mass spectrometry. Body mass index and total body fat were measured, and abdominal subcutaneous and visceral adipose tissue (aSAT and VAT) were assessed using magnetic resonance imaging. Using multivariable-adjusted linear regression analyses, we analysed the associations of BMI, TBF, aSAT and VAT with levels of urinary α-TOH metabolites, adjusted for confounders. We observed no evidence for associations between body fat measures and serum α-TOH. Higher BMI and TBF were associated with lower urinary levels of TLHQ (0.95 [95%CI: 0.90, 1.00] and 0.94 [0.88, 1.01] times per SD, respectively) and with lower TLHQ relative to CEHC (0.93 [0.90, 0.98] and 0.93 [0.87, 0.98] times per SD, respectively). We observed similar associations for VAT (TLHQ: 0.94 [0.89, 0.99] times per SD), but not for aSAT.

Conclusions: Opposite to our research hypothesis, higher abdominal adiposity was moderately associated with lower levels of oxidized α-TOH metabolites, which might reflect lower vitamin E antioxidative activity in individuals with higher abdominal fat instead.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.numecd.2021.05.001DOI Listing
July 2021

The associations of leptin and adiponectin with the metabolic syndrome in an Indonesian and a Dutch population.

Nutr Metab Cardiovasc Dis 2021 07 27;31(8):2426-2435. Epub 2021 May 27.

Department of Clinical Epidemiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands.

Background And Aims: At the same BMI, Asian populations develop cardiometabolic complications earlier than Western populations. We hypothesized that a different secretion of the adipocyte-derived hormones leptin and adiponectin plays a role and investigated the associations of the two hormones with the metabolic syndrome (MetS) in an Indonesian and a Dutch population.

Methods And Results: We performed cross-sectional analyses of the Netherlands Epidemiology of Obesity Study (n = 6602) and the SUGAR Scientific Programme Indonesia-Netherlands Study (n = 1461). We examined sex-stratified associations of leptin and adiponectin with MetS, using multivariate logistic regression including adjustment for total body fat. The mean (SD) leptin (mcg/L) were 4.7 (6.0) in Indonesian men, 18.6 (12.0) in Indonesian women, 9.1 (7.7) in Dutch men, and 23.4 (17.4) in Dutch women. The mean (SD) adiponectin (mg/L) were 5.7 (5.4), 7.5 (7.1), 6.6 (3.3), and 11.3 (4.9), respectively. Within the same BMI category, leptin concentrations were similar in the two populations, whereas adiponectin was lower in the Indonesian population. Per SD of leptin, adjusted prevalence odds ratios (ORs, 95%CI) of MetS were 0.9 (0.6-1.2) in Indonesian men, 1.1 (0.9-1.4) in Indonesian women, 2.2 (1.6-2.8) in Dutch men, and 1.2 (1.0-1.5) in Dutch women. Per SD of adiponectin, the ORs were 0.9 (0.7-1.2), 0.8 (0.7-1.0), 0.6 (0.6-0.8), and 0.4 (0.4-0.5), respectively.

Conclusions: Despite lower adiponectin levels, adiponectin was not related to the MetS in the Indonesian population and can not explain their increased cardiometabolic risk at the same BMI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.numecd.2021.05.012DOI Listing
July 2021

Health and treatment outcomes of patients with hemophilia in the Netherlands, 1972-2019.

J Thromb Haemost 2021 Jun 12. Epub 2021 Jun 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Introduction: We conducted six cross-sectional nationwide questionnaire studies among all patients with hemophilia in the Netherlands from 1972 until 2019 to assess how health outcomes have changed, with a special focus on patients >50 years of age.

Methods: Data were collected on patient characteristics, treatment, (joint) bleeding, joint impairment, hospitalizations, human immunodeficiency virus and hepatitis C infections, and general health status (RAND-36).

Results: In 2019, 1009 patients participated, of whom 48% had mild, 15% moderate, and 37% severe hemophilia. From 1972 to 2019, the use of prophylaxis among patients with severe hemophilia increased from 30% to 89%. Their median annual bleeding rate decreased from 25 to 2 bleeds. Patients with severe hemophilia aged <16 years reported joint impairment less often over time, but in those aged >40 years joint status did not improve. In 2019, 5% of all 1009 patients were positive for the human immunodeficiency virus. The proportion of patients with an active hepatitis C infection drastically decreased from 45% in 2001 to 2% in 2019 due to new anti-hepatitis C treatment options. Twenty-five percent had significant liver fibrosis even after successful therapy. Compared to the general male population, patients aged >50 years reported much lower scores on the RAND-36, especially on physical functioning.

Discussion/conclusion: Our study shows that increased use of prophylactic treatment and effective hepatitis C treatment have improved joint health and nearly eradicated hepatitis C infection in patients with hemophilia in the Netherlands. However, patients still suffer from hemophilia-related complications, especially patients aged >50 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15424DOI Listing
June 2021

Objectively Measured Physical Activity and Body Fatness: Associations with Total Body Fat, Visceral Fat, and Liver Fat.

Med Sci Sports Exerc 2021 May 28. Epub 2021 May 28.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Department of Nutrition and Movement Sciences, Maastricht University Medical Center, Maastricht, The Netherlands MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: It remains unclear to what extent habitual physical activity and sedentary time are associated with visceral fat and liver fat. We studied substitution of sedentary time with time spent physically active and total body fat (TBF), visceral adipose tissue (VAT) and hepatic triglyceride content (HTGC) in middle-aged men and women.

Design: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, physical activity was assessed in 228 participants using a combined accelerometer and heart rate monitor. Total body fat was assessed by the Tanita bio-electrical impedance, VAT by MRI and HTGC by proton-MR spectroscopy. Behavioural intensity distribution was categorized as sedentary time (ST), time spent in light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA). To estimate the effect of replacing 30 minutes/day of ST with 30 minutes/day LPA or MVPA, we performed isotemporal substitution analyses, adjusted for sex, age, ethnicity, education, the Dutch Healthy Diet index, and smoking.

Results: Included participants (41% men) had a mean (SD) age of 56 (6) years and spent 88 (56) minutes in MVPA and 9.0 hours (2.1) of ST. Replacing 30 minutes/day of ST with 30 minutes of MVPA was associated with 1.3% less TBF (95% CI: -2.0, -0.7), 7.8 cm2 less VAT (-11.6, -4.0) and 0.89 times HTGC (0.82, 0.97). Replacement with LPA was not associated with TBF (-0.03 %; -0.5, 0.4), VAT (-1.7 cm2; -4.4, 0.9) or HTGC (0.98 times; 0.92, 1.04).

Conclusions: Reallocation of time spent sedentary with time spent in MVPA, but not LPA, was associated with less total body fat, and visceral and liver fat. These findings contribute to the development of more specified guidelines on sedentary time and physical activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1249/MSS.0000000000002712DOI Listing
May 2021

Metabolomics dissection of depression heterogeneity and related cardiometabolic risk.

Psychol Med 2021 Jun 3:1-10. Epub 2021 Jun 3.

Department of Psychiatry, Amsterdam Public Health Research Institute, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, The Netherlands.

Background: A recent hypothesis postulates the existence of an 'immune-metabolic depression' (IMD) dimension characterized by metabolic dysregulations. Combining data on metabolomics and depressive symptoms, we aimed to identify depressions associated with an increased risk of adverse metabolic alterations.

Method: Clustering data were from 1094 individuals with major depressive disorder in the last 6 months and measures of 149 metabolites from a 1H-NMR platform and 30 depressive symptoms (IDS-SR30). Canonical correlation analyses (CCA) were used to identify main independent metabolite-symptom axes of variance. Then, for the replication, we examined the association of the identified dimensions with metabolites from the same platform and cardiometabolic diseases in an independent population-based cohort (n = 6572).

Results: CCA identified an overall depression dimension and a dimension resembling IMD, in which symptoms such as sleeping too much, increased appetite, and low energy level had higher relative loading. In the independent sample, the overall depression dimension was associated with lower cardiometabolic risk, such as (i.e. per s.d.) HOMA-1B -0.06 (95% CI -0.09 - -0.04), and visceral adipose tissue -0.10 cm2 (95% CI -0.14 - -0.07). In contrast, the IMD dimension was associated with well-known cardiometabolic diseases such as higher visceral adipose tissue 0.08 cm2 (95% CI 0.04-0.12), HOMA-1B 0.06 (95% CI 0.04-0.09), and lower HDL-cholesterol levels -0.03 mmol/L (95% CI -0.05 - -0.01).

Conclusions: Combining metabolomics and clinical symptoms we identified a replicable depression dimension associated with adverse metabolic alterations, in line with the IMD hypothesis. Patients with IMD may be at higher cardiometabolic risk and may benefit from specific treatment targeting underlying metabolic dysregulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0033291721001471DOI Listing
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Triglyceride-lowering LPL alleles combined with LDL-C-lowering alleles are associated with an additively improved lipoprotein profile.

Atherosclerosis 2021 07 9;328:144-152. Epub 2021 May 9.

Dept. Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Dept. Internal Medicine, Div. Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.

Background And Aims: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles.

Methods: We quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two × two design with the group with genetically-influenced high TG and LDL-C as a reference.

Results: Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 × 10) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower.

Conclusions: Our findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2021.04.015DOI Listing
July 2021

Ongoing and future COVID-19 vaccine clinical trials: challenges and opportunities.

Lancet Infect Dis 2021 May 18. Epub 2021 May 18.

Department of Medicine, University of Jaffna, Jaffna, Sri Lanka.

Large-scale deployment of COVID-19 vaccines will seriously affect the ongoing phases 2 and 3 randomised placebo-controlled trials assessing SARS-CoV-2 vaccine candidates. The effect will be particularly acute in high-income countries where the entire adult or older population could be vaccinated by late 2021. Regrettably, only a small proportion of the population in many low-income and middle-income countries will have access to available vaccines. Sponsors of COVID-19 vaccine candidates currently in phase 2 or initiating phase 3 trials in 2021 should consider continuing the research in countries with limited affordability and availability of COVID-19 vaccines. Several ethical principles must be implemented to ensure the equitable, non-exploitative, and respectful conduct of trials in resource-poor settings. Once sufficient knowledge on the immunogenicity response to COVID-19 vaccines is acquired, non-inferiority immunogenicity trials-comparing the immune response of a vaccine candidate to that of an authorised vaccine-would probably be the most common trial design. Until then, placebo-controlled, double-blind, crossover trials will continue to play a role in the development of new vaccine candidates. WHO or the Council for International Organizations of Medical Sciences should define an ethical framework for the requirements and benefits for trial participants and host communities in resource-poor settings that should require commitment from all vaccine candidate sponsors from high-income countries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(21)00263-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131060PMC
May 2021

Agreement of aptamer proteomics with standard methods for measuring venous thrombosis biomarkers.

Res Pract Thromb Haemost 2021 May 4;5(4):e12526. Epub 2021 May 4.

Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands.

Background: Venous thromboembolism (VTE) is a complex disease with an incidence rate of about 1 in 1000 per year. Despite the availability of validated biomarkers for VTE, unprovoked events account for 50% of first events. Therefore, emerging high-throughput proteomics are promising methods for the expansion of VTE biomarkers. One such promising high-throughput platform is SomaScan, which uses a large library of synthetic oligonucleotide ligands known as aptamers to measure thousands of proteins.

Objective: The aim of this study was to evaluate the viability of the aptamer-based SomaScan platform for VTE studies by examining its agreement with standard laboratory methods.

Methods: We examined the agreement between eight established VTE biomarkers measured by SomaScan and standard laboratory immunoassay and viscosity-based instruments in 54 individuals (27 cases and 27 controls) from the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism study. We performed the agreement analysis by using a regression model and predicting the estimates and the 95% prediction interval (PI) of the laboratory instrument values using SomaScan values.

Results: SomaScan measurements exhibited overall poor agreement, particularly for D-dimer (average fit, 492.7 ng/mL; 95% PI, 110.0-1998.2) and fibrinogen (average fit, 3.3 g/L; 95% PI, 2.0-4.7).

Conclusion: Our results indicate that SomaScan measurement had poor agreement with the standard laboratory measurements. These results may explain why some genome-wide association studies with VTE proteins measured by SomaScan did not confirm previously identified loci. Therefore, SomaScan should be considered with caution in VTE studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/rth2.12526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110437PMC
May 2021

The effect of physical activity level and exercise training on the association between plasma branched-chain amino acids and intrahepatic lipid content in participants with obesity.

Int J Obes (Lond) 2021 07 2;45(7):1510-1520. Epub 2021 May 2.

Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.

Aims: To evaluate whether the association between plasma branched-chain amino acids (BCAA) and intrahepatic lipid (IHL) was affected by physical activity level. Furthermore, to investigate if a conventional exercise training program, a subcategory of physical activity, could lower plasma BCAA along with alterations in IHL content in patients with type 2 diabetes (T2DM) and people with nonalcoholic fatty liver (NAFL).

Methods: To investigate the effect of physical activity on the association between plasma BCAA and IHL content, linear regression analyses were performed in 1983 individuals from the Netherlands Epidemiology of Obesity (NEO) stratified by physical activity frequency. Furthermore, the effect of a 12-week supervised combined aerobic resistance-exercise program on plasma BCAA, insulin sensitivity (hyperinsulinemic-euglycemic clamp), and IHL (proton-magnetic resonance spectroscopy (H-MRS)) was investigated in seven patients with T2DM, seven individuals with NAFL and seven BMI-matched control participants (CON).

Results: We observed positive associations between plasma valine, isoleucine and leucine level, and IHL content (1.29 (95% CI: 1.21, 1.38), 1.52 (95% CI: 1.43, 1.61), and 1.54 (95% CI: 1.44, 1.64) times IHL, respectively, per standard deviation of plasma amino acid level). Similar associations were observed in less active versus more active individuals. Exercise training did not change plasma BCAA levels among groups, but reduced IHL content in NAFL (from 11.6 ± 3.0% pre-exercise to 8.1 ± 2.0% post exercise, p < 0.05) and CON (from 2.4 ± 0.6% pre-exercise to 1.6 ± 1.4% post exercise, p < 0.05), and improved peripheral insulin sensitivity in NAFL as well by ~23% (p < 0.05).

Conclusions: The association between plasma BCAA levels and IHL is not affected by physical activity level. Exercise training reduced IHL without affecting plasma BCAA levels in individuals with NAFL and CON. We conclude that exercise training-induced reduction in IHL content is not related to changes in plasma BCAA levels.

Trial Registration: Trial registry number: NCT01317576.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41366-021-00815-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236400PMC
July 2021

Sampling Strategies for Internal Validation Samples for Exposure Measurement-Error Correction: A Study of Visceral Adipose Tissue Measures Replaced by Waist Circumference Measures.

Am J Epidemiol 2021 09;190(9):1935-1947

Statistical correction for measurement error in epidemiologic studies is possible, provided that information about the measurement error model and its parameters are available. Such information is commonly obtained from a randomly sampled internal validation sample. It is however unknown whether randomly sampling the internal validation sample is the optimal sampling strategy. We conducted a simulation study to investigate various internal validation sampling strategies in conjunction with regression calibration. Our simulation study showed that for an internal validation study sample of 40% of the main study's sample size, stratified random and extremes sampling had a small efficiency gain over random sampling (10% and 12% decrease on average over all scenarios, respectively). The efficiency gain was more pronounced in smaller validation samples of 10% of the main study's sample size (i.e., a 31% and 36% decrease on average over all scenarios, for stratified random and extremes sampling, respectively). To mitigate the bias due to measurement error in epidemiologic studies, small efficiency gains can be achieved for internal validation sampling strategies other than random, but only when measurement error is nondifferential. For regression calibration, the gain in efficiency is, however, at the cost of a higher percentage bias and lower coverage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/aje/kwab114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408354PMC
September 2021

Normal and reference values for cardiovascular magnetic resonance-based pulse wave velocity in the middle-aged general population.

J Cardiovasc Magn Reson 2021 04 19;23(1):46. Epub 2021 Apr 19.

Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Background: Aortic stiffness, assessed through pulse wave velocity (PWV), is an independent predictor for cardiovascular disease risk. However, the scarce availability of normal and reference values for cardiovascular magnetic resonance imaging (CMR) based PWV is limiting clinical implementation. The aim of this study was to determine normal and reference values for CMR assessed PWV in the general population.

Methods: From the 2,484 participants of the Netherlands Epidemiology of Obesity (NEO) study that have available CMR-PWV data, 1,394 participants free from cardiovasculard disease, smokers or treatment for diabetes, hypertension or dyslipidaemia were selected (45-65 years, 51% female). Participants were divided into sex, age and blood pressure (BP) subgroups. Normal values were specified for participants with a BP < 130/80 mmHg and reference values for elevated BP subgroups (≥ 130/80 and < 140/90 mmHg; and ≥ 140/90 mmHg). Differences between groups were tested with independent samples t-test or ANOVA. Due to an oversampling of obese individuals in this study, PWV values are based on a weighted analysis making them representative of the general population.

Results: Normal mean PWV was 6.0 m/s [95% CI 5.8-6.1]. PWV increased with advancing age and BP categories (both p < 0.001). There was no difference between sex in normal PWV, however in the BP > 140/90 mmHg women had a higher PWV (p = 0.005). The interpercentile ranges were smaller for participants < 55 years old compared to participants ≥ 55 years, indicating an increasing variability of PWV with age. PWV upper limits were particularly elevated in participants ≥ 55 years old in the high blood pressure subgroups.

Conclusion: This study provides normal and reference values for CMR-assessed PWV per sex, age and blood pressure category in the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12968-021-00739-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054386PMC
April 2021

Adherence to direct oral anticoagulant treatment for atrial fibrillation in the Netherlands: A surveillance study.

Pharmacoepidemiol Drug Saf 2021 Aug 4;30(8):1027-1036. Epub 2021 May 4.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Adherence to direct oral anticoagulants (DOACs) in patients with atrial fibrillation in every day practice may be less than in clinical trials.

Aims: To assess adherence to DOACs in atrial fibrillation patients in every day practice and identify predictors for non-adherence.

Methods: Individual linked dispensing data of atrial fibrillation patients who used DOACs were obtained from the Foundation for Pharmaceutical Statistics covering the Netherlands between 2012 and 2016. One year adherence to DOAC was calculated for initial DOAC as proportion of days covered (PDC) ≥80% and the association between clinical variables and adherence was assessed using logistic regression. In addition, we measured non-persistence, that is, patients who completely stopped their initial DOAC within 1 year follow-up.

Results: A total of 4797 apixaban-, 20 454 rivaroxaban- and 18 477 dabigatran users were included. The mean age was 69 years (n = 43 910), which was similar for the DOAC types. The overall proportion of patients with PDC ≥80% was 76%, which was highest for apixaban- (87%), followed by dabigatran- (80%) and rivaroxaban (69%) users. Multivariable analyses revealed that age ≤60 years, no concomitant drug use were predictors for non-adherence. Of atrial fibrillation patients who continued treatment, 97% had a PDC ≥80%, compared with only 56% for those who discontinued their DOAC treatment within 1 year.

Conclusions: Non-adherence to DOACs was associated with age ≤60 years and no concomitant drugs use. Non-adherence was higher in patients who later discontinued DOAC treatment. Results of our study support research into interventions to improve adherence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pds.5242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360064PMC
August 2021

Thoughtful selection and use of scientific terms in clinical research: the case of 'pragmatic' trials.

J Investig Med 2021 06 22;69(5):1056-1058. Epub 2021 Mar 22.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

Clinical research is a discipline prone to the use of technical terms that may be particularly at risk for misunderstanding given the complex interpretation that is required. In this century, what is happening with the word 'pragmatic' when describing a randomized controlled trial (RCT) with medicines deserves a public reflection. Explanatory trials are conducted in ideal conditions to assess the comparative efficacy of interventions and are useful to explain whether interventions work. Pragmatic trials are those conducted in a way that resembles usual clinical practice conditions to assess the comparative effectiveness of interventions in a manner directly applicable for decision-makers. This, however, did not prevent 36% of authors of placebo-controlled, or prelicensing trials to identify their medicines RCTs as pragmatic in the title of their articles. The current situation is such that scientific literature has accepted that 'pragmatic' can convey the original meaning-that obtained in trials mimicking usual clinical practice-and a distorted one-that is focused on streamlining any trial procedure. Those involved in clinical trials should emphasize the importance of precision in the use of terms when describing RCTs through standardized solutions when possible. Unless clinical trial stakeholders agree when it would be correct to label an RCT as pragmatic, in a short period of time the term will be in danger of becoming meaningless. It is suggested that the Enhancing the Quality and Transparency of Health Research (EQUATOR) network, the Consolidated Standards of Reporting Trials (CONSORT) group and the International Committee of Medical Journal Editors (ICMJE) could address this topic and provide a consensus way forward.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jim-2021-001789DOI Listing
June 2021

Glucocorticoid use and risk of first and recurrent venous thromboembolism: self-controlled case-series and cohort study.

Br J Haematol 2021 Jun 21;193(6):1194-1202. Epub 2021 Mar 21.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Glucocorticoid treatment increases venous thromboembolism (VTE) risk. Whether this is due to the medication or the underlying disease, or affects the risk of VTE recurrence, has been difficult to determine. The aim of our present study was to quantify the risk for first and recurrent VTE associated with oral glucocorticoids use, considering the underlying disease. A total of 2547 patients with VTE from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study were linked to the Dutch Pharmaceutical Statistics register. The risk of first VTE during periods of exposure with oral glucocorticoids was estimated by the self-controlled case series method and that of recurrent VTE was examined in a cohort design. The incidence rate ratio (IRR) of first VTE in the period of glucocorticoid treatment was 3·51 [95% confidence interval (CI) 2·55-4·80]. This IRR was 2·53 (95% CI 1·10-5·72) in the week before treatment started, 5·28 (95% CI 2·89-9·53) in the first 7 days of treatment, remained elevated afterwards and decreased to 1·55 (95% CI 0·85-3·12) after 6 months, as compared to unexposed periods. The hazard ratio for recurrence was 2·72 (95% CI 1·64-4·78) in treatment periods as compared with no treatment. The increased risk of VTE associated with oral glucocorticoid treatment is due to a combined effect of the treatment and the underlying disease, remaining high during the first months of prescription.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251551PMC
June 2021

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BMC Med 2021 Mar 18;19(1):69. Epub 2021 Mar 18.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Background: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.

Methods: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.

Results: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.

Conclusions: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-021-01939-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971964PMC
March 2021
-->